In breast cancer cells, cytoplasmic localization of the estradiol receptor alpha (ER alpha) regulates estradiol-dependent S phase entry. We identified a nuclear export sequence (NES) in ER alpha and show that its export is dependent on both estradiol-mediated phosphatidylinositol-3-kinase (PI3K)/AKT activation and chromosome region maintenance 1 (CRM1). A Tat peptide containing the ER alpha NES disrupts ER alpha-CRM1 interaction and prevents nuclear export of ER alpha- and estradiol-induced DNA synthesis. NES-ER alpha mutants do not exit the nucleus and inhibit estradiol-induced S phase entry; ER alpha-dependent transcription is normal. ER alpha is associated with Forkhead proteins in the nucleus, and estradiol stimulates nuclear exit of both proteins. ER alpha knockdown or ER alpha NES mutations prevent ER alpha and Forkhead nuclear export. A mutant of forkhead in rhabdomyosarcoma (FKHR), which cannot be phosphorylated by estradiol-activated AKT, does not associate with ER alpha and is trapped in the nucleus, blocking S phase entry. In conclusion, estradiol-induced AKT-dependent phosphorylation of FKHR drives its association with ER alpha, thereby triggering complex export from the nucleus necessary for initiation of DNA synthesis and S phase entry.
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Abbondanza, C
Rossi, V
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Rossi, V
Roscigno, A
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Roscigno, A
Gallo, L
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Gallo, L
Belsito, A
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Belsito, A
Piluso, G
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Piluso, G
Medici, N
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Medici, N
Nigro, V
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Nigro, V
Molinari, AM
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Molinari, AM
Moncharmont, B
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Moncharmont, B
Puca, GA
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
机构:Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA
Alt, JR
Cleveland, JL
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机构:Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA
Cleveland, JL
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Hannink, M
Diehl, JA
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Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USAUniv Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA
机构:
Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Abbondanza, C
Rossi, V
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h-index: 0
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Rossi, V
Roscigno, A
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Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Roscigno, A
Gallo, L
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h-index: 0
机构:
Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Gallo, L
Belsito, A
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h-index: 0
机构:
Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Belsito, A
Piluso, G
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h-index: 0
机构:
Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Piluso, G
Medici, N
论文数: 0引用数: 0
h-index: 0
机构:
Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Medici, N
Nigro, V
论文数: 0引用数: 0
h-index: 0
机构:
Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Nigro, V
Molinari, AM
论文数: 0引用数: 0
h-index: 0
机构:
Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Molinari, AM
Moncharmont, B
论文数: 0引用数: 0
h-index: 0
机构:
Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
Moncharmont, B
Puca, GA
论文数: 0引用数: 0
h-index: 0
机构:
Univ Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, ItalyUniv Naples 2, Fac Med & Chirurg, Ist Patol Gen & Oncol, I-80138 Naples, Italy
机构:Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA
Alt, JR
Cleveland, JL
论文数: 0引用数: 0
h-index: 0
机构:Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA
Cleveland, JL
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机构:
Hannink, M
Diehl, JA
论文数: 0引用数: 0
h-index: 0
机构:
Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USAUniv Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA